Purpose :
Despite poor performance, topical drops are by far the most widely used therapy for many ocular diseases. Dynamic barriers including the rapid tear turnover, lacrimal drainage, and the vasculature and lymphatics of the conjunctiva all conspire to prevent the majority of topically applied therapeutics from reaching their site of action. We propose the use of mucoadhesive self-assembling micelles as a solution to the obvious problems facing topical ocular drug delivery. In this study, cyclosporin A (CycA) was encapsulated and used to treat an animal model of dry eye disease (DED).

Methods :
pLA-b-p(MAA-PBA) copolymers were synthesized by RAFT polymerization and contained a spectrum of PBA mole percentages. Copolymer composition and molecular weight were determined using pNMR. Micelles were formed by precipitation into purified water from acetone. Micelle size was determined using dynamic light scattering (DLS). Mucoadhesion was determined using surface plasmon resonance (SPR) with bovine mucin and simulated tear fluid, as well as an in vivo assay where fluorescein was covalently bound to the outer shell of the micelle, and residence time was recorded. CycA release from micelles was determined using high performance liquid chromatography, as well as an in vivo rescue of benzalkonium chloride induced DED.

Results :
DLS determined the diameter of the micelles range from 35nm to 65nm as the mole percentage of PBA is increased from 0% to 30%. CycA was entrapped within the LMP micelles by dissolving both components in acetone followed by addition into purified water at a ratio of 20 mg copolymer to 3 mg CycA. All micelles showed entrapment efficiencies greater than 99.8% and excellent release characteristics. SPR confirmed a strong relationship between the mole percentage of PBA and mucoadhesion. After a standard battery of cell viability testing which showed no adverse reaction using human corneal epithelial cells, these micelles were tested in vivo using Sprague-Dawley rats by dropping their eyes for a period of 10 days, showing excellent biocompatibility.